Department of Medical Oncology, the First Hospital of China Medical University, Shenyang 110001, China.
Int J Mol Sci. 2013 Dec 16;14(12):24399-411. doi: 10.3390/ijms141224399.
5-Fluorouracil (5-FU) is an essential component of anticancer chemotherapy against gastric cancer. However, the response rate of single drug is still limited. The ubiquitin ligase Cbl-b is a negative regulator of growth factor receptor signaling and is involved in the suppression of cancer cell proliferation. However, whether Cbl-b could affect 5-FU sensitivity remains unclear. The present study showed that Cbl-b knockdown caused higher proliferation concomitant with the decrease of apoptosis induced by 5-FU treatment in gastric cancer cell. Further mechanism investigation demonstrated that Cbl-b knockdown caused significant increase of phosphorylation of EGFR, ERK and Akt, decrease of mitochondrial membrane potential, and increase of expression ratio of Bcl-2/Bax. These results suggest that Cbl-b enhances sensitivity to 5-FU via EGFR- and mitochondria-mediated pathways in gastric cancer cells.
5-氟尿嘧啶（5-FU）是治疗胃癌的抗癌化疗的重要组成部分。然而，单一药物的反应率仍然有限。泛素连接酶 Cbl-b 是生长因子受体信号的负调节剂，参与抑制癌细胞增殖。然而，Cbl-b 是否能影响 5-FU 的敏感性尚不清楚。本研究表明，Cbl-b 敲低导致更高的增殖，同时伴随着 5-FU 处理诱导的凋亡减少。进一步的机制研究表明，Cbl-b 敲低导致 EGFR、ERK 和 Akt 的磷酸化显著增加，线粒体膜电位降低，Bcl-2/Bax 的表达比例增加。这些结果表明，Cbl-b 通过 EGFR 和线粒体介导的途径增强胃癌细胞对 5-FU 的敏感性。
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